Cancer Chemotherapy I Flashcards
Problem with using cytotoxic chemo against cancer
- Potential for harming dividing non-cancer cells (nonspecific). Cancer
cells are not always very different from normal cells. They could
differ in only a single pathway. Metastasis is usually when there
start to be a lot of differences. - Doesn’t kill all of the cancer cells. Resting (non-dividing) cancer cells
and cancer stem cells can get past this. Once all of the dividing cells
are killed and the treatment is stopped they can start to proliferate. - Drug resistance.
Common adverse effects associated with cytotoxic anti cancer drugs
- Immune system is turned down.
- GI disturbance.
- Hair loss.
- Bone marrow suppression (immunosuppression, anemia, thrombocytopenia).
- Nausea.
- Mouth sores.
-Impaired wound healing. Whenever wound healing occurs you need to have
cells migrating from the surrounding area to where the wound is. Cancer
drugs can prevent this. -Teratogenic-Cells in the mouth and GI tract are usually shed off relatively
frequently, so stopping these from dividing will cause disturbances. -Immune cells are not always dividing, but say that there is an invader and they need to divide, then cytotoxic drugs will prevent this and you can get some bad side effects.
Strategies for targeting cancer
There are two main strategies for cancer therapies:
Cytotoxic and targeted approaches. Majority of cancer treatments involve
cytotoxic drugs.
DNA Damaging Agents
Alkylating Agents
- Platinumcompounds- MOAs:
1. Cause misincorporation of nucleotides during replication leading to
mutations which inhibit cell growth or cause cell death. They can also
cause mutations in normal cells. This can lead to reappearance of cancer
after treatment. In some cases this is due to drug resistance, in others it
may be due to new mutations created by the drugs themselves.
2. Directly block DNA replication via cross-linking mechanisms.
3. Causes dsDNA breaks, activating DNA damage cell cycle checkpoints,
resulting in apoptosis.
Chemical Crosslinking of DNA with Bifunctional Alkylating Agents
-cause inter and intra strand cross-linking. Alkylating agents preferentially target guanine bases. Can be on the same or different strands. Halts DNA rep and can cause ds breaks.
Alkylation and Crosslinking of DNA
Chloride leaving groups are part of the mechanism. Cyclic intermediate is created which rearranges to form carbonium ion that can specifically interact with guanine bases (ring nitrogen). You then get an alkylation reaction. The second chloride can then leave and the same reaction can occur to link the two bases.
Nitrogen Mustards
- Cyclophosphamide: Used for breast cancer, leukemia, ovarian cancer
- Estramustine:Used for pancreatic cancer
- drug selectivity may have to do with limited access to cell,specific metabolic reactions within the cells, or maybe the lifespan of the drug in different areas
of the body.-Structure resembles a steroid. The steroid structure works to stop hormone signaling. Blocks
the production of testosterone which is elevated in pancreatic cancer.
Since alkylating agents bind to protein and RNA along with DNA, how did they test what the main mech was?
- Hypothesis:Comparedwithproteinsand RNA, nitrogen mustards show a preference for the #7 nitrogen of deoxyguanine
- Evidence:Somebacterialstrainsareresistant to N-mustards. Treat both sensitive and resistant bacteria with radiolabeled N- mustard. Isolate and hydrolyze DNA. Sensitive strains yield alkylated di-guanyl nucleosides. Little or no radioactivity is associated with DNA in resistant bacteria
Activation of The Nitrogen Mustard Cyclophosphamide
Activation of The Nitrogen Mustard Cyclophosphamide by- Prodrug that is activated
by P450. P450Hepatic cytochrome
oxidase is P450
-Acrolein byproduct is
very toxic to liver. Mesna renders
the acrolein nontoxic. So its given along
with the drug.
Cisplatin
Cisplatin
Structure: a central platinum atom surrounded by 2 chlorine atoms and 2 ammonia groups
- MOA: Generates intra-strand DNA cross-links. So between bases of the same
strand.
- Used to treat a wide variety of sold tumor cancers
- Side effects (other than the typical ones) include nephrotoxicity, ototoxicity, peripheral neuropathy, and reduced fertility
- not very effective for leukemias. As a general rule, most treatments
that work for tumors wont work for leukemias, and vice versa.
Antimetabolites
Once again hitting enzymes of the thymidine synthesis pathway. Targets dihydrofolate reductase. Dihydrofolate reductase carries out primarily two main reactions. One is dihydrofolate to tetrahydrofolate. The other is folate acid converted to dihydrofolate. Both steps are inhibited by methotrexate.
How to treat autoimmune without meds?
there is some evidence that helminth infections can reduce some symptoms of autoimmune disorders.
Methotrexate
- Dissociation half time is several weeks
- Used to treat wide range of solid tumors
- Resistance develops rapidly
- Low doses used to treat autoimmune disorders
- MOA competitive inhibitor of dihydrofolate reductase, resulting in deficiet of tetrahydrofolate with susequent block in thymidine synthesis. resistance develops due to cells LARGLY upregulating the gene content
of dihydrofolate reductase gene expression by 100 fold.
What does methotrexate resemble.
similarity in structure between folic acid and methotrexate.
5-Fluorouracil
•Analog of the nucleotide base uracil
•Activated by cellular metabolism
•MOA: irreversible inhibitor of thymidylate synthase. Not a competitive inhibitor
but it does bind to the active site, so its also not an allosteric inhibitor.
Since its irreversible, it is a non-competitive inhibitor.
•Used to treat multiple types of solid tumor cancers
- needs to be turned into the nucleoside by cellular base salvaging pathway.
